Molecular pharmacotargets in donor cardiac graft preservation: mechanisms and translational perspectives

Although heart transplantation remains the definitive therapy for end-stage heart failure, its widespread application is constrained by conventional static cold storage (SCS), where prolonged cold ischemia inflicts irreversible injury. Current preservation solutions lack pharmacologically active components capable of targeting unique hypothermia-induced damage, including lipid phase separation, mitochondrial decay, and restricted succinate clearance, which collectively trigger a devastating oxidative stress burst upon reperfusion. To address this clinical bottleneck, this review systematically deciphers the pathophysiology of cold ischemic injury, framing the discussion around the metabolic distinctions between warm and cold ischemia. We synthesize pivotal molecular interventions targeting oxidative stress cascades, programmed cell death networks (such as apoptosis and ferroptosis), sterile inflammation, organelle impairment, and epigenetic dysregulation, while clarifying their specific applicable scenarios. Crucially, we evaluate the therapeutic superiority of natural products derived from plants, fungi, and marine animals as multi-target synergistic agents, while confronting translational barriers involving their low bioavailability and complex regulatory approval. Ultimately, we outline actionable paradigms to bridge this translational gap, highlighting nanocarrier-based advanced drug delivery and the utilization of in vitro mechanical perfusion as an active therapeutic platform. Integrating these tools with multi-omics profiling allows for personalized, donor-specific preservation strategies. Together, this comprehensive review provides essential theoretical insight and practical guidance to optimize donor graft viability and advance the field of myocardial protection worldwide.